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הוראה בנושאי טיפול תרופתי בסרטן. נושאים כלליים: מטרות הטיפול, הערכת תגובה אובייקטיבית וסובייקטיבית , הערכת רעילות, מחקר קליני, קינטיקה של הגידול, קביעת מינון ותדירות הטיפול ערך: פרופ’ נ. חיים , מאי 2003, עודכן-ספטמבר 2004 כתובת לשאלות והערות: [email protected]

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הוראה בנושאי טיפול תרופתי בסרטן

נושאים כלליים: מטרות הטיפול, הערכת תגובה אובייקטיבית וסובייקטיבית , הערכת רעילות, מחקר קליני, קינטיקה של הגידול, קביעת מינון ותדירות הטיפול

ערך: פרופ’ נ. חיים , מאי 2003, עודכן-ספטמבר 2004

כתובת לשאלות והערות:

[email protected]

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מטרות הטיפול הכימותרפי
  • טיפול להשגת ריפוי מלא (curative )
  • טיפול פליאטיבי (palliative )
  • טיפול משלים (adjuvant ) וטיפול neoadjuvant (או induction chemotherapy )
slide3
מדדים אובייקטיביים להערכת תגובה לטיפול
  • בדיקה גופנית: מדידת גודל בלוטות, גושים , כבד וכו’
  • בדיקות הדמיה:CT , אולטרסאונד, MRI , מיפויים
  • סמני גידול (tumor markers ):

CEA, CA-125, BETA-HCG, ALPHA-FETO PROTEIN

  • הערכת תגובה ע”י ביופסיה חוזרת
slide4
הגדרת התגובה האובייקטיבית לטיפול
  • תגובה (הפוגה) מלאה - complete response
  • תגובה (הפוגה) חלקית- partial response
  • התייצבות המחלה- stable disease
  • התקדמות המחלה- tumor progression
slide5
WHO & RRCIST (response evaluation criteria in solid tumors) criteria for evaluation of response to chemotherapy
  • מהם?
  • מה ההגדרה של ממצאים, הניתנים להערכה?
  • הגדרת תגובה חלקית על פי כ”א
  • תשובות בשקופיות הבאות
evaluation of response to chemotherapy
Evaluation of response to chemotherapy
  • Miller AB et al. Reporting results of cancer treatment. Cancer 47: 207-14, 1981
  • Therasse P et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92: 205-16, 2000
who criteria for evaluation of response
WHO criteria for evaluation of response

Miller AB et al. Reporting results of cancer treatment. Cancer 47: 207-14,1981

measurability of disease:

measurable, bidimensional

measurable, unidimensional

nonmeasurable, evaluable

recist response evaluation criteria in solid tumors guidelines
RECIST (response evaluation criteria in solid tumors) guidelines

(collaboration between EORTC, NCI & NCI of Canada-RECIST working group)

measurability of disease:

measurable lesion: 20 mm or more with conventional techniques or 10 mm or more with spiral CT.

Nonmeasurable lesion: all smaller lesions and truly nonmeasurable (e.g. bone lesions, leptomeningeal disease, effusions, etc).

The term “evaluable” in reference to measurability will not be used.

who definition of partial response for bidimentional lesion s
WHO definition of partial response for bidimentional lesion(s)

Miller AB et al. Reporting results of :cancer treatment. Cancer 47: 207-14, 1981

single lesion: greater than or equal to 50% decrease in tumor area (multiplication of longest diameter by the greatest perpendicular diameter).,

multiple lesions: a 50% or more decrease in the sum of the products of the multiple lesions

(there can be no appearance of new lesions or progression of any lesion.)

response evaluation who vs recist new response evaluation criteria in solid tumors criteria
Response evaluation: WHO vs. RECIST (new response evaluation criteria in solid tumors)criteria

PR:

WHO: 50% decrease in sum of products; confirmed at 4 wks

RECIST: 30% decrease in sums of longest diameters; confirmed at 4 wks

PD:

WHO: 25% increase in sum of products

RECIST: 20% increase in sums of longest diameters

evaluation of response to imatinib mesylate glivec in gist
Evaluation of response to imatinib mesylate (glivec) in GIST

Bleeding during treatment with glivec may cause an increase in the size of measurable lesions. Thus, standard response evaluation criteria, such as those recommended by the WHO or RECIST may be inappropriate to evaluate early treatment effects. This can be done by 18-FDG-PET (functional evaluation) or by MRI (extent of tumor necrosis).

Reichardt P et al. J Clin Pathol 57: 215-7, 2004

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הערכה סוביקטיבית של מצב החולה
  • מצב תפקודי ( Performance Status ):

(ECOG-ZUBROD/WHO)

  • דרגה 0- אין שום הגבלה, דרגה 1- מוגבל בפעילות פיזית קשה, דרגה 2 - מוגבל בעבודה ובפעולות יומיומית שגרתיות, אך נמצא מחוץ למיטה ברוב הזמן, דרגה 3- רוב הזמן במיטה, דרגה 4-מרותק למיטה
  • שאלון איכות חיים (Quality of Life)
  • clinical benefit
therapeutic index
Therapeutic index

Therapeutic index is the relation between the desired and undesired effects of therapy.

slide15
סוגי מחקר קליני
  • Definition & goals of phase I, II, & III
  • DLT, MTD, recommended phase II dose (RPTD)
  • Initial dose & dose escalation in phase I
  • Alpha & beta errors (in phase II)
  • תשובות בשקופיות הבאות
slide16
סוגי מחקר קליני
  • Phase I : שלב ראשון לאחר המחקרים הפרה-קליניים. מטרתו בעיקר לקבוע את המנה המרבית הנסבלת

maximal tolerated dose)=MTD(

של תרופה חדשה או טיפול חדשני.

  • Phase II : מטרתו לבדוק את הפעילות של התרופה או של הטיפול במחלה מסוימת.
  • Phase III : מטרתו להשוות את התרופה החדשה (או את הטיפול החדש) לתרופה או לטיפול המקובלים. המחקר הוא prospective randomized trial .
phase i trial
Phase I trial
  • מינון התחלתי:

one -tenth of the mouse equivalent LD10

  • מינון ברמה מסוימת ניתן בד”כ לקבוצות של 3 חולים. מעלים את המינון בקבוצה הבאה לפי סולם Fibronacci ( כלומר: 100%, 65%, 50%, 40%, ואח”כ 33%).
  • עולים במינון עד שמגיעים ל- MTD (בד”כ המנה שגורמת ל- DLTב-2/3 או ב- 2 או 3 מתוך 6 חולים).המינון ברמה הנמוכה יותר מ- MTD הוא ה-RPTD.
phase ii trial design
Phase II trial design

Alpha & beta errors:

Alpha error is a measure of the probability of accepting an inactive drug (false-positive).

Beta error- a measure of the probability of rejecting an active drug (false-negative)

sample size in phase II:

assuming that 20% is a true response rate:the study will be terminated if no response is seen after 14 cases (beta=0.05).

(if 1 responds-add 45 pts for beta=0.05)

phase iv trials
Phase IV Trials
  • Designed for postmarketing surveillance of approved drugs (the final validation before commercialization and routine use).
slide20
מושגים שונים במחקרים קליניים
  • הסבר
  • Randomization,
  • stratification,
  • single-blinded, double -blinded,
  • crossover design,
  • power,
  • intention -to- treat analysis,
  • subgroup analysis
  • confidence intervals,
  • meta-analysis
parameters end points in cancer chemotherapy
Parameters (end-points) in cancerchemotherapy
  • Objective response rate (and type of response, i.e. CR or PR)
  • Duration of response
  • Time to tumor progression (or time to treatment failure)
  • Survival
  • Quality of life
  • Cost
levels of evidence and grade for recommendations
Levels of Evidence and Grade for Recommendations
  • Level I: Evidence is obtained from meta-analysis of multiple , well-designed, controlled studies. Randomized trials have to be with low false-positive and false negative errors (high power).
  • Levels II-IV…….
  • Level V:Evidence is from case reports and clinical examples.
  • Grade of Recommendation: A-D….
relative and absolute risk reduction
Relative and absolute risk reduction

Example:

10-year survival without treatment = 92%

10-year survival with treatment = 96%

Relative reduction of 10-year mortality =50%

Absolute reduction of 10-year mortality =4%

skipper gompertzian models
Skipper & Gompertzian models
  • הסבר את 2 המודלים הנ”ל להתפתחות הגידול
  • תשובה בשקופיות הבאות
skipper laws
Skipper laws
  • Doubling time of proliferating cancer cells is constant, forming a straight line on a semi logarithmic plot.
  • Cell kill by drugs follows first-order kinetics (log cell kill), which means that a given drug concentration applied for a defined time period will kill a constant fraction of the total cell population (e.g., 2-log kill=99% of tumor cells).

(Skipper laws are derived from murine (L1210) experiments and only apply to cells in the proliferating compartment).

gompertzian growth curve
Gompertzian growth curve

The growth fraction of the tumor is not constant but decreases exponentially.

Growth curve is sigmoid (and not linear-as in Skippers` model) in a semi-logarithmic plot: at first, cells number increases slowly because of the small number of cells,... then-rapidly..., reaching a maximum rate at approx. one-third of max. tumor size…then slower (due to anoxia…exit of cells to G0…).

(unlike the Gompertzian model, Skipper`s laws apply only to the proliferating fraction)

goldie and coldman model
Goldie and Coldman model
  • הסבר עקרונות. מהי הדרך העדיפה לתת כימותרפיה על פי מודל זה?
  • תשובה בשקופית הבאה
goldie and coldman model1
Goldie and Coldman model

A mathematical model that applies to the development of resistance to anticancer drugs by cancer cells without prior exposure to these drugs:

  • spontaneous mutations to resistance occur at a predictable frequency.Therefore, probability of mutations increases with tumor size.
  • When non-homogeneous tumor cells are subjected to selective drugs, sensitive tumor cells will be destroyed while subpopulations of resistant cells will survive.
  • Paradoxically, sensitive normal tissues never develop resistance.
  • The model predicts that the maximal chance for cure occurs when all available effective drugs are given simultaneously.
dose intensity dose density
Dose-intensity & Dose-density
  • הסבר
  • compare 90 mg/m2 every 3 weeks, vs. 30 mg/m2/week with regard to dose intensity & dose-density.
  • תשובות בשקופיות הבאות
dose intensity dose density1
Dose-intensity & Dose-density
  • Dose-intensity:

מנת התרופה ליחידת זמן:(מינון /שטח גוף/ יחידת זמן)

  • Dose-density (Dose-dense chemotherapy):

מתן מנות מוגברות במרווחים קצרים ככל האפשר

contd

dose intensity dose density2
Dose-intensity & Dose-density

For the same dose intensity of 90 mg/m2 every 3 weeks, 30 mg/m2/week gives a greater dose density than the 3-weekly administration.

norton simon hypothesis
Norton-Simon hypothesis
  • “The growth curves that best fit these data had a sigmoid (Gompertzian) shape, and simulations of chemotherapy effects predicted that the simple manipulation of compressing the conventional schedule of drug administration (dose-dense therapy) would achieve greater efficacy by minimizing the regrowth of tumor cells between treatment cycles”.

Piccart-Gebhart MJ, Mathematics and oncology: a mach for life? J Clin Oncol 21: 1425-8, 2003 (editorial)

tolerability of dose dense chemotherapy with gcsf breast cancer
Tolerability of dose-dense chemotherapy with GCSF-breast cancer

Citron ML et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer:….CALGB. J Clin Oncol 21: 1431-39, 2003

  • AC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2) and Paclitaxel (175 mg/m2)
  • Regular regimen (q 3 weeks) was compared to dose-dense regimen (q 2 weeks+GCSF support).
  • Treatment was well tolerated. Severe neutropenia was less frequent in patients who received the dose-dense regimens.
tolerability of dose dense chemotherapy with gcsf non hodgkin s lymphoma
Tolerability of dose-dense chemotherapy with GCSF-non Hodgkin`s lymphoma

-Blayney DW et al. J Clin Oncol 21: 2466-73, 2003

-Pfreundschuh M et al. Blood (2004 Mar 11)

(published ahead of print)

  • Regular CHOP (given every 3 weeks) was compared to 2 weekly (=dose intense=CHOP-14) CHOP with GCSF support.
  • Treatment with 2 weekly CHOP can be safely administered with a comparable toxicity profile.
superiority of dose dense therapy in breast cancer
Superiority of dose-dense therapy in breast cancer

Citron ML et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer:….CALGB. J Clin Oncol 21: 1431-39, 2003

Dose-dense chemotherapy improved disease free survival and overall survival.

body surface area
Body-surface area
  • מה הבסיס לשימוש בשטח הגוף כבסיס לחישוב מנות תרופות? עד כמה מוצדק? תן דוגמא(ות)
  • תשובות בשקופיות הבאות
body surface area1
Body-surface area
  • “data that supported the introduction of BSA- based dose-calculation in the late 1950s (sulfadiazine, acetylsalicylic acid…renally excreted drugs) were reviewed…..the routine use of BSA for dose calculation should be reevaluated”.

Gurney H. J Clin Oncol 14:2590-611, 1996 (Review)

body surface area2
Body-surface area
  • Gurney HP. J Clin Oncol 16: 2299, 1998 (Epirubicin)

“These results led us to question the use of BSA for epirubicin dose calculation”.

Mathijssen RHJ et al. J Clin Oncol 20: 81, 2001 (Irinotecan)

“BSA is not a predictor of CPT-11 clearance or SN-38 pharmacokinetics “

de Jongh FE et al. J Clin Oncol 19: 3733, 2001 (Cisplatin)

“…no rationale for continuing BSA-based dosing of cisplatin was found….”

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